This invention relates to the treatment of degenerative diseases of the central nervous system, such as those associated with aging and senile dementia of the Alzheimer's type (hereinafter referred to by the abbreviation SDAT). In particular, this invention also relates to methods for preparing pharmaceuticals useful in the treatment of nervous system degeneration, pharmaceutical compositions useful for said treatment and to methods for facilitating the growth and repair of damaged nerve tissue, including brain cells.
SDAT, commonly called Alzheimer's disease, is a progressive degenerative disorder of the central nervous system leading to severe disturbances in perception, memory, and overall neurological function. In advanced cases, gross pathological alterations in the structure of the brain itself are visible. A large body of current research is directed toward elucidating the causes and mechanisms of this disease and toward halting or reversing its debilitating progress.
The sex hormones, the androgens and estrogens, are known to counter various non-neurological symptoms of aging. However, problems typically arise that preclude prolonged use of the hormones. These problems include endometrial bleeding, prostatic hypertrophy, and signs of carcinogenesis.
One precursor of the androgens and estrogens, dehydroepiandrosterone (hereinafter referred to by the abbreviation DHEA) or its sulfate (hereinafter referred to by the abbreviation DHEAS) has been shown to have a number of therapeutic effects. Serum levels of DHEA decrease over the life span of a human being. It has been shown, for example, that administration of DHEA or DHEAS can reduce the incidence of breast cancer in mice, can reduce obesity in such mice, and that after prolonged administration of DHEA, the mice that have received the compound appear to be younger than mice that have not. Science News 119, 39 (Jan. 17, 1981). This has led to speculation that DHEA compounds may retard the aging process. See also A. Rosenfeld, Omni 59 et seq. (August, 1982) and A. Rosenfeld, Science 81 2, 20-21 (November, 1981). The use of DHEA compounds to treat diabetes has been reported. See, e.g., U.S. Pat. Nos. 4,507,289 and 4,518,595. DHEA has also been used in topical applications for preventing dry skin. U.S. Pat. No. 4,496,558. However, the action of DHEA and related compounds on the nervous system of mammals has been substantially unexplored.
Current research indicates that the symptoms of SDAT reflect the inability of the organism to continue to compensate for continuing degenerative changes in the biochemical machinery of the organism and the cell. Ideally, a living organism and its parts are cybernetic: the various elements effectively communicate with and respond to each other and to the environment in an adaptive way to maintain an ideal, steady-state condition.
Manifestations of aging of the nervous system--whether one looks at neuropathologic, physiologic, neurochemical or behavioral aspects--appear to reflect a final common path taken by organisms when behavioral options ordinarily available to achieve adaptive responses are precluded by degeneration of the neural machinery. Even during the early "normal" adult period, degenerative changes probably are taking place to some extent, but are being compensated for by activities of redundant neural elements and by adjustments in neural feedback and modulator systems. However, eventually pathologic changes may become sufficiently extensive so that the latter activities are inadequate and the social behavior and physiological responses of the severely affected individual become maladaptive and, in the case of humans, survival becomes dependent upon extensive use of artificial social and medical support systems. The endstage pathologies observed are characterized by degenerative changes in cells in many brain regions and are associated with losses of neuronal cells, decreases in neuronal processes in surviving cells, and increases in glial elements. Viral and bacterial infections, dietary deficiencies and imbalances, cardiovascular, metabolic, and endocrine disorders, anoxia, various types of space occupying lesions and traumata, and toxins, may, by themselves, cause degenerative changes or they may predispose to such changes in response to subsequent cerebral insult or injury. Accelerated degeneration of neural, endothelial, neuroendocrine, and endocrine elements together with incoordination in the networks of relations among the cellular components of the immune system, and coincident disruption of neurovascular relations and breakdown of the blood brain barrier in the affected regions, could predispose to the developement of both circulating and cellular autoantibodies to various cellular and extracellular components in the disrupted regions. This may lead to enhanced cellular destruction and deposition of the relatively indigestible debris of immune complexes in capillaries and extracellular sites. Another consequence of perturbation of the immune system might be immunosuppression with resultant activation of latent viruses destructive to the nervous system.
Cells, like organisms, are integrated organizations of a highly heterogeneous nature. They contain thousands of different chemical substances of varying degrees of complexity in physical and chemical interactions with each other in various subcellular organelles and compartments, many of which are morphologically distinguishable by light or electron microscopy. The structures of cell membranes and of membranes of the intracellular organelles have varying stabilities. The membranes have differing degrees of exchangeability with their immediate environment, and the enzyme systems associated with them catalyze some of the chemical reactions by which the internal needs of the individual cells are subserved as well as by which the relations with the extracellular environment are maintained.
When ligands attach to their specific receptors on particular membranes, cascades of biochemical reactions are set in motion in a coordinated way so that in a brief period the cells of which they are a part react appropriately in a manner compatible with their individual behavioral repertoire. Any havoc wrought by the messages the ligands bring is repaired, and the cellular machinery may be altered in such a way as to integrate the messages that the ligands bring. Manifestations of aging--pathologic, physiologic, or biochemical--appear to reflect a common path taken by cells when the mechanisms ordinarily available to achieve adaptive responses, such as those alluded to above, are precluded by degenerative changes in the cellular machinery. Degenerative changes always must be taking place to some extent in any given cell, but are being compensated for by redundant cellular elements and by cybernetic adjustments among the varieties of degradative and synthetic mechanisms. As in the case of the whole organism, when this is no longer possible, aging is said to take place and cell death eventually occurs.
It may be concluded that aging phenomena, at all levels from social to molecular, result in decyberneticization, i.e., disruption of meaningful communication channels between components of relevant members of interlocking systems, so that eventually overtly observable adaptive behaviors are not possible and the organism can no longer function or survive.
Because SDAT of the sporadic type almost always occurs coextensively with aging, many pathological features of decyberneticization are shared. However, SDAT should not be considered entirely in the same category as normal attritional types of aging because, in addition to the above general types of aging changes, important genetic components exist in familial SDAT (there are pedigrees showing what appears to be an autosomal dominant transmission of the disorder) and idiosyncratic reactions to ubiquitously present environmental factors also may play an important role. Behavioral, pathologic, and biochemical data are consistent with the hypothesis that in SDAT the degenerative changes observed in several brain regions are correlated with initial malfunction and subsequent degeneration of terminals of neurons whose somata lie in regions of the brainstem core and whose fibers project to many structures both above and below their location. In SDAT there often is a specific loss of neurons in the basal nucleus of Meynert (Whitehouse, et al., Ann. Neural. 10, 122 (1981)) and sometimes in the locus oceruleus (Bondareff, et al., Neurology 32, 164 (1982)), which are the major sources of extrinsic cholinergic and noradrenergic inputs, respectively, projecting widely and diffusely upon all telencephalic structures. There is evidence that the hippocampus, a region of the brain known to play a key role in memory formation, essentially may be removed from brain circuitry by lesions at its input and output sites (Hyman, et al., Science 225, 1168 (1984)).
Both in SDAT and in "normal" aging, changes in membranes of capillary endothelial cells may influence the rate of entry of substances into the central nervous system by diffusion, pinocytosis, or carrier-mediated transport; or the rate of pumping of K.sup.+ ions out of the brain extracellular compartment may be changed. Indeed, it has been suggested from detailed electron microscopic observations that capillary degeneration with the formation of amyloid fibrils may be the primary change in the genesis of senile plaques of SDAT (Miyakawa, et al, Virchows Arch. [Cell Pathol.]40, 121 (1982)). Effects on neural membranes may produce decreases in their conductile properties, changes in release characteristics from terminals of neurotransmitters and modulators, alterations in the sensitivity of pre- and postsynaptic receptors to the action of the latter, and changes in degrees of electrotonic communication between neurons via gap junctions. At the onset of the disease, a whole host of cybernetic adjustments would be expected to be taking place, structural and enzymatic, so that metabolic steady states different from those found before would exist at cellular and tissue levels, and new transactional states would be found at the systems level in the CNS. This process may continue as the disease progresses, until breakdowns occur in one or another rate-limiting process, leading to progressive deterioration and finally fatal loss of adaptive function.
Thus, if the rate-limiting steps or events in an organism's adaptive and compensatory response to biological and biochemical changes associated with SDAT can be identified, one may treat the symptoms and arrest the degenerative progress of the disease by removing the rate-limiting factors.